Liposomal Doxorubicin: the Sphingomyelin/Cholesterol System Significantly Enhances the Antitumor Efficacy of Doxorubicin

Doxorubicin (DOX) has a cytotoxic effect on many tumor cells; however, its clinical application is limited owing to its strong side effects. Although Doxil® reduces the cardiotoxicity of free DOX, it has also introduced a new dose-limiting toxicity. In a previous study, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified onto the surface of DOX-loaded liposomes to target tumor-associated macrophages (TAMs), further improving the efficacy of DOX-loaded liposomes over that of Doxil®. Meanwhile, the good retention characteristics and promising antitumor ability of sphingomyelin/cholesterol (SM/CH) system for water-soluble drugs have attracted wide attention. Therefore, we aimed to use SA-CH as the target and hydrogenated soybean phosphatidylcholine (HSPC) or egg sphingomyelin (ESM) as the membrane material to develop a more stable DOX-loaded liposome with stronger antitumor activity. The liposomes were evaluated for particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release, long-term storage, cytotoxicity, cellular uptake, pharmacokinetics, tumor targetability, and in vivo antitumor activity. In the liposomes prepared using HSPC/CH, sialic acid (SA) modification considerably increased the accumulation of DOX-loaded liposomes in the tumor, thus exerting a better antitumor effect. However, SA modification in DOX-ESL (SA-CH-modified DOX-loaded liposomes prepared by ESM/CH) destroyed the strong retention effect of the ESM/CH system on DOX, resulting in a reduced antitumor effect. Notably, DOX-ECL (DOX-loaded liposome prepared by ESM/CH) had the optimal storage stability, lowest toxicity, and optimal antitumor effect due to better drug retention properties. Thus, the ESM/CH liposome of DOX is a potential drug delivery system. Sketch of the effect of two DOX-loaded liposomes with hydrogenated soybean phospholipid (HSPC) and egg sphingomyelin (ESM) as lipid membrane material and surface-modified SA derivative on tumor growth inhibition.

[1]  Wenjing Wu,et al.  Neutrophils as emerging immunotherapeutic targets: Indirect treatment of tumors by regulating the tumor immune environment based on a sialic acid derivative-modified nanocomplex platform. , 2022, International journal of pharmaceutics.

[2]  Yuqing Su,et al.  Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil/monocyte infiltration for tumor therapy. , 2021, Acta biomaterialia.

[3]  Xinrong Liu,et al.  Sialic acid conjugate-modified liposomal platform modulates immunosuppressive tumor microenvironment in multiple ways for improved immune checkpoint blockade therapy. , 2021, Journal of controlled release : official journal of the Controlled Release Society.

[4]  A. Puri,et al.  Role of Stealth Lipids in Nanomedicine-based drug carriers. , 2021, Chemistry and physics of lipids.

[5]  Mengyang Liu,et al.  Neutrophils as Emerging Immunotherapeutic Targets: Indirect Treatment of Tumors by Regulating the Tumor Immune Environment Based on a Sialic Acid Derivative-Modified Nanocomplex Platform , 2022, International journal of pharmaceutics.

[6]  Xiang-chun Shen,et al.  Co-delivery of doxorubicin and epacadostat via heparin coated pH-sensitive liposomes to suppress the lung metastasis of melanoma. , 2020, International journal of pharmaceutics.

[7]  Xinrong Liu,et al.  Terminating the renewal of tumor-associated macrophages: a sialic acid-based targeted delivery strategy for cancer immunotherapy. , 2019, International journal of pharmaceutics.

[8]  Yanzhi Song,et al.  Exhausting tumor associated macrophages with sialic acid‐polyethyleneimine‐cholesterol modified liposomal doxorubicin for enhancing sarcoma chemotherapy , 2019, International journal of pharmaceutics.

[9]  Johannis P Kamerling,et al.  Exploration of the Sialic Acid World , 2018, Advances in Carbohydrate Chemistry and Biochemistry.

[10]  Xinrong Liu,et al.  Redox- and pH-Sensitive Glycan (Polysialic Acid) Derivatives and F127 Mixed Micelles for Tumor-Targeted Drug Delivery. , 2018, Molecular pharmaceutics.

[11]  J. Grabowska,et al.  CD169+ Macrophages Capture and Dendritic Cells Instruct: The Interplay of the Gatekeeper and the General of the Immune System , 2018, Front. Immunol..

[12]  Gordon D. Brown,et al.  C-type lectins in immunity and homeostasis , 2018, Nature Reviews Immunology.

[13]  Yuqing Su,et al.  Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)–octadecylamine conjugate for lung cancer treatment , 2018, Drug Delivery.

[14]  Donghua Di,et al.  Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity. , 2017, International journal of pharmaceutics.

[15]  Yonglian Zhang,et al.  C-type lectins facilitate tumor metastasis , 2016, Oncology letters.

[16]  Yihui Deng,et al.  A review on phospholipids and their main applications in drug delivery systems , 2015 .

[17]  P. Allavena,et al.  Tumor-associated macrophages: functional diversity, clinical significance, and open questions , 2013, Seminars in Immunopathology.

[18]  Soodabeh Davaran,et al.  Liposome: classification, preparation, and applications , 2013, Nanoscale Research Letters.

[19]  A. Gabizon,et al.  Polyethylene Glycol-Coated (Pegylated) Liposomal Doxorubicin , 2012, Drugs.

[20]  T. De,et al.  Leishmania Donovani Cell Surface Sialoglycans Regulate Susceptibility for Siglec Mediated Macrophage Invasion and Parasite Survival , 2012 .

[21]  Andreas Wagner,et al.  Liposome Technology for Industrial Purposes , 2010, Journal of drug delivery.

[22]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[23]  P. Allavena,et al.  Tumor‐associated macrophages (TAM) as major players of the cancer‐related inflammation , 2009, Journal of leukocyte biology.

[24]  Lisa Brannon-Peppas,et al.  Active targeting schemes for nanoparticle systems in cancer therapeutics. , 2008, Advanced drug delivery reviews.

[25]  Laurence Zitvogel,et al.  Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy , 2007, Nature Medicine.

[26]  K. Edwards,et al.  Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity. , 2005, Journal of pharmaceutical sciences.

[27]  K. Skubitz.  Phase II Trial of Pegylated-Liposomal Doxorubicin (Doxil™) in Renal Cell Cancer , 2002, Investigational New Drugs.

[28]  B. Overmoyer,et al.  Pegylated Liposomal Doxorubicin (Doxil®) Versus Doxorubicin for First-Line Treatment of Metastatic Breast Cancer , 2002 .

[29]  M. Ranson,et al.  Caelyx (stealth liposomal doxorubicin) in the treatment of advanced breast cancer. , 2001, Critical reviews in oncology/hematology.

[30]  M. Bally,et al.  A Comparison of Liposomal Formulations of Doxorubicin with Drug Administered in Free Form , 2001, Drug safety.

[31]  J. Slotte,et al.  Sphingomyelin-cholesterol interactions in biological and model membranes. , 1999, Chemistry and physics of lipids.

[32]  T. E. Thompson,et al.  Sphingomyelin: biophysical aspects. , 1999, Chemistry and physics of lipids.

[33]  M. Bally,et al.  Comparison of different hydrophobic anchors conjugated to poly(ethylene glycol): effects on the pharmacokinetics of liposomal vincristine. , 1998, Biochimica et biophysica acta.

[34]  M. Bally,et al.  Liposomal Vincristine: The Central Role of Drug Retention in Defining Therapeutically Optimized Anticancer Formulations , 1998 .

[35]  A. Gabizon,et al.  Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. , 1997, Drugs.

[36]  P. Working,et al.  Pharmacological-toxicological expert report. CAELYX. (Stealth liposomal doxorubicin HCl). , 1996, Human & experimental toxicology.

[37]  M. Bally,et al.  Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. , 1995, British Journal of Cancer.

[38]  D. Needham,et al.  Structure and cohesive properties of sphingomyelin/cholesterol bilayers. , 1992, Biochemistry.

[39]  P. Singal,et al.  Subcellular effects of adriamycin in the heart: a concise review. , 1987, Journal of molecular and cellular cardiology.

[40]  K. Mitropoulos,et al.  Effect of liposomal phospholipid composition on cholesterol transfer between microsomal and liposomal vesicles. , 1986, The Biochemical journal.

[41]  T. Allen,et al.  Effect of liposome size and drug release properties on pharmacokinetics of encapsulated drug in rats. , 1983, The Journal of pharmacology and experimental therapeutics.

[42]  G. Gregoriadis,et al.  Stability of small unilamellar liposomes in serum and clearance from the circulation: the effect of the phospholipid and cholesterol components. , 1982, Life sciences.

[43]  D. V. Von Hoff,et al.  Risk factors for doxorubicin-induced congestive heart failure. , 1979, Annals of internal medicine.

[44]  J. Pitha,et al.  A clinicopathologic analysis of adriamycin cardiotoxicity , 1973, Cancer.

[45]  A. Bangham,et al.  NEGATIVE STAINING OF PHOSPHOLIPIDS AND THEIR STRUCTURAL MODIFICATION BY SURFACE-ACTIVE AGENTS AS OBSERVED IN THE ELECTRON MICROSCOPE. , 1964, Journal of molecular biology.